Patient-reported outcomes (PROs) are considered an integral part of cancer clinical research and drug development, as an important complement to other clinical endpoints to understand the benefits of treatment but also risks, since cancer diseases and their respective treatment regimens are associated with significant negative symptoms, side effects, and functional limitations. Such information may be then used in regulatory and healthcare decision-making to draw conclusions regarding the benefit–risk balance. PROs refer to outcomes coming directly from patients about how they feel or function in relation to a health condition and its therapy, without interpretation by healthcare professionals; they are based on patient’s perception of a disease and its treatment covering multi-dimension measures of symptoms, quality of life, health status, adherence to treatment, and satisfaction with treatment [1,2,3]. Capturing patients’ perspectives in the oncology setting is an opportunity to collect information on patient’s perception of the disease and its treatment, including the impact on symptoms (e.g. pain, fatigue), perception of daily functioning (e.g. physical, social), and health-related quality of life (HRQOL).

This editorial aims at reporting on the current global landscape on the use of PROs for the evaluation of anti-cancer treatments, integrated with other relevant endpoints, both in clinical trials and clinical practice, to better inform clinical decision-making and healthcare policy.

1 PROs in Oncology Clinical Trials

PROs have become a central component in oncology clinical trials. From a regulatory perspective, the importance of incorporating the patient’s point of view on health status is currently reflected in the European Medicines Agency (EMA) guidelines [1, 2] and United States (US) Food and Drug Administration (FDA) guidance [3]. To better measure the patient’s perception, robust safety and tolerability data are essential in cancer therapeutic studies. With this aim, a multi-stakeholder working group including drug sponsors, regulators from the US and Europe, researchers, and patients developed a new definition of tolerability that incorporates the patient’s perception by measuring treatment burden and patient-reported symptomatic toxicity and function [4]. Overall, patient-reported outcome measures (PROMs) may provide clinically relevant information about patients’ symptoms, functioning, and well-being that is not adequately captured by conventional anti-tumour efficacy and safety data. However, PROs instruments should be relevant, reliable, validated, and responsive to change [1]. Findings measured by a well-defined and reliable PROs instrument in appropriately designed investigations can be used to support a claim in a medical product [3]. However, the EMA is more likely to grant claims in the area of HRQOL or functioning, whereas the FDA is largely limited to claims of improvement in symptoms [5].

Both the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) have proposed standardised approaches to evaluate clinical trial results by using scores to evaluate the Magnitude of Clinical Benefit Scale (ESMO) or Net Health Benefit Score (ASCO), which include evidence regarding improved or delayed deterioration in HRQOL in addition to survival endpoints and toxicity [6]. Patient’s perception data are relevant at different stages: during clinical trial design (selection of endpoints), during benefit–risk assessment (patient preferences), and in the post-marketing for pharmacovigilance (adverse drug reaction reporting). PROs data are important also from the Health Technology Assessment (HTA) perspective for the cost-effectiveness evaluation, although robust methodology for study planning, quality of data collection, appropriate statistical analysis, standard reporting, and clear interpretation of results are required. The importance of PROs data in HTA is increasing for oncology therapies, influencing market access, reimbursement, and pricing negotiations. From research in 14 markets, it emerged that PROs evidence appears to have greater influence outside the US and affects decision-making for 47% of US payers and 78% of ex-US payers, with greater weight in major markets [7]. Payers consistently rated improvements in HRQOL and functional status as being extremely important, while US payers also rated improvements in symptom severity or frequency as extremely important.

Despite growing recognition of the value of PROs data for the development of improved cancer therapies, implementation remains challenging. Indeed, there is no standard approach to collecting, analysing, or interpreting PROs data in clinical trials, and methodological challenges have reduced the impact of PROs data on regulatory decisions, such as PRO measures (PROMs) selection, data collection, management and analysis, missing data, timing of assessments, lack of a priori specification of the expected effect size, and lack of post-progression data. Collection of PROMs in oncology clinical trials is recommended by regulatory authorities since they may provide evidence to support medicines approval, labelling, and marketing claims. For inclusion in labelling, PROs should be fully validated and have clinical relevance; in addition, from a statistical perspective, they should be robust measures, e.g. secondary endpoints controlled for type I error [2]. Thus, the amount and kind of evidence that should be provided are the same as for any other claim based on clinical data to evaluate the treatment benefit [3]. In past years, most medicines granted approval by the EMA and FDA included PROs in pivotal trials as secondary endpoints; however, only a few indications included label claims in the Summary of Product Characteristics (SmPC), due to non-blinding of the study treatment, measure selection not being considered optimal, methodological robustness, and unclear/limited clinical relevance [8].

In oncology studies, benefits related to tumour growth and overall survival are often accompanied by significant toxicity and disease-related symptoms; therefore, symptomatic adverse events, physical function, and health status are considered key contributors to the effect of a therapy on HRQOL [9]. Most current measures quantify these concepts in a single, static, multi-item instrument with several domains, such as the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 Items (EORTC QLQ-C30), EuroQol 5-dimensional questionnaire (EQ-5D), and Functional Assessment of Cancer Therapy–General (FACT-G) with FACT disease-specific modules. These questionnaires, used irrespective of disease stage or therapies, may not be precise and appropriate to capture patient’s perception, while separate measurements, in the context of emerging contemporary instruments, may provide a more adaptable strategy across the range of oncological disease and therapies. In recent years, tools to measure PROs have evolved, with validated measures to assess core outcomes and item libraries to allow measurement of trial-specific and treatment-specific issues. Static questionnaires are a fixed set of items intended to measure a specific concept or a group of related concepts; they can be generic or disease-condition specific, and have the advantage of being often psychometrically validated to generate reliable scores. However, computer-adaptive testing (CAT) has the advantage that the items can be selected from the bank to form customised short scales or can be administered in a sequence and length determined by a computer programmed for precision and clinical relevance. In addition, CAT offers advantages such as immediate data entry, ease of scoring, immediate plotting of results, and real-time clinical monitoring [10]. A combination of static questionnaires and item libraries may be important to create a balanced, flexible, and modular approach to PROs assessment, to address key health domains that are relevant for specific contexts, interventions, and target populations. To guide users on the design and implementation of this customised PROMs, a working group including multiple stakeholders developed recommendations for the use of item libraries in oncology trials [11].

PROMs can be used at individual patient–clinician interactions (to report how the patient feels, functions, and lives), to help identify symptoms and inform patient monitoring and management, and aggregated for use as real-world evidence [12]. Efforts to capture and report PROs data should be inclusive and equitable, addressing the diverse needs of all patients with the condition of interest, including groups historically and currently underserved by research [13]. PROs data from cancer clinical trials can provide valuable evidence to inform shared decision-making, labelling claims, clinical guidelines, and health policy, although PROs content in clinical trial protocols is often suboptimal. With this aim, several guidelines have been implemented to provide recommendations for items that should be addressed and included to ensure high-quality data. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)–PRO guidelines provided recommendations for issues that should be addressed, including specific research questions and rationale, hypotheses, domains used to evaluate the intervention, data collection plan, strategies to minimise missing data, statistical analysis methods, administration, and setting [14]. In addition, the SPIRIT-PRO explanation and elaboration paper provided information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template [15]. Finally, user-friendly tools were developed to support the involvement of patient partners in making informed contributions to the development of PROs aspects of clinical trial protocols, in accordance with the SPIRIT-PRO extension guidelines [16]. The Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials – Innovative Medicines Initiative (SISAQOL-IMI) Consortium has been convened by the EORTC with the aim to establish guidance so that PROs can be used in a methodologically sound way, analysed in a statistically adequate manner, and intelligibly presented to ensure high study quality and better comparability of results across clinical trials [17]. The Consolidated Standards of Reporting Trials (CONSORT) statement aims to improve the reporting of PROs data, allowing robust interpretation of the results from clinical trials. Five CONSORT-PRO checklist items have been recommended for clinical trials in which PROs are primary or important secondary endpoints. These recommendations urge that the PROs be identified as a primary or secondary outcome in the abstract, that a description of the hypothesis and relevant domains be provided, that evidence of the PROs instrument’s validity and reliability be provided or cited, that the statistical approaches for dealing with missing data be explicitly stated, and that PRO-specific limitations of study findings and generalisability of results to other populations and clinical practice be discussed [18].

Variations in how PROMs are scored, scaled, and reported make interpretation challenging and limit their use in clinical practice. Therefore, several recommendations aim to optimise the accurate and meaningful interpretation of PROs data [19]. Although PROs can inform healthcare decisions and can be used for monitoring symptoms to provide timely care tailored to individual needs, several ethical issues have been raised for their use. The PROs ethics guidelines provided recommendations for ethical issues that should be addressed in PROs clinical research to ensure high-quality PROs data while minimising participant risk, burden, and harm and protecting participant and researcher welfare [20].

2 PROs in Oncology Clinical Practice

Across the last decades, the point of view in oncology has progressively changed from “disease-centred care” to “patient-centred care”. The “disease-centred” model defines the patients by their disease, sorting patients into rigid diagnostic as well as treatment pathways, embracing the “one-size fits all” approach; while in the “patient-centred care” model, oncological patients are considered as individuals affected by a unique disease with a personalised medical history and health needs. In this context, PROs could represent a valuable tool for clinicians to raise patients’ satisfaction and to reinforce the patient–doctor alliance, thereby increasing patients’ engagement with the therapeutic decisional process [21]. The aforementioned aspects should be considered particularly relevant for oncological patients, with potential implications in the optimisation of therapeutic strategy, quality of life, and outcomes. Of note, to achieve their beneficial effects on patient management, PROs should be considered by clinicians as part of the medical encounter, and not as a substitute for patient interviews and symptoms assessment [22]. Another open issue is the identification of the more appropriate time points to integrate PROs in the real-world setting, considering that patients’ evaluations vary over time and might be affected by when they are performed (e.g. the perception of quality of life and pain in relation to the response achieved to the ongoing therapy line in patients with advanced disease). Indeed, PROs may potentially be used as a screening tool at diagnosis as a starting point in the oncology history of a patient, as well as after a surgical resection with the curative aim to customise patients’ follow-up, and after the end of a follow-up to evaluate possible supportive care for cancer survivors [23]. Moreover, providing metastatic patients with PROs at several fixed time points during the therapy course could be useful to allocate the patients to the intervention needed thanks to the obtained measurements [24]. In this light, PROs, by adequately assessing the subjective benefit of treatment from the patient's perspective and their symptoms and perceptions, may provide a reliable and useful foundation to guide patients’ medical course with an approach more tailored to specific patient demands [25, 26]. In recent years, there has been also an increase in studies aimed at establishing thresholds for clinically important levels of scores for PROMs to improve interpretability of the questionnaire results and foster use in daily clinical practice. With this aim, the EORTC Quality of Life Group study provided thresholds for clinical importance for the functioning and symptom scales of the EORTC QLQ-C30 [27, 28].

Overall, PROs are a powerful tool for clinical practice that directly measures patients’ perspectives, enabling providers to tailor care to patients’ needs and priorities. Indeed, implementing PROs as part of routine care can help to identify and address healthcare problems, increase efficiency, and improve patient outcomes [29]. However, there is no one-size-fits-all approach to integrating PROs into clinical practice, and PROs systems can vary according to factors such as healthcare setting, PROs system goals, and patient characteristics. For successful implementation of routine PROs assessments, an adequate strategy is needed that includes all types of users (e.g. patients, healthcare personnel, and organisations) and gives guidance for the implementation process. EORTC measures have shown to be beneficial for routine care, as they cover both symptoms and impact on functioning, are well accepted by patients, can improve communication between healthcare personnel and patients, and enable facilitated shared medical decision-making and personalised care [30].

Although PROs data have potential benefits for patients, facilitating tailored care to individual needs, barriers persist to the collection, analysis, interpretation, and integration in clinical practice. Common barriers to routine use can include individual, structural, and organisational factors such as low familiarity with the concept of PROs, workflow of healthcare professionals, and technical infrastructure. The potential burden on respondents may have an impact on the completeness and quality of the collected data. To reduce respondent burden, a consensus statement by an international multi-stakeholder group was implemented, including a list of recommendations divided into three categories, i.e. rationale and schedule of assessments, measure selection, and measure delivery [31]. Organisations implementing PROMs need to invest time and resources in designing the PROMs strategy (including how the data would be used for clinical purposes) and preparing for PROMs use (including demonstrating to clinicians the value of PROMs, delivering training, and developing electronic systems) [32]. Whilst the benefits of using PROs and PROMs to guide real-time patient care are well established, they have not been also adopted by many oncology institutions worldwide for several reasons at the patient level (time, incapacity, and difficulty using electronic devices), at the health professional level (lack of time and knowledge to meaningfully interpret and integrate PROs data into their clinical practice), and at the service level (difficulties integrating PROs and PROMs into clinical workflows and inadequate information technology infrastructures for easy PROs collection) [33].